1.beta.-Methylcarbapenem derivatives have been of great interest for their excellent antibacterial activities against a wide range of microorganisms including Gram positive and Gram negative bacteria, especially against Cephem-resistant bacteria, and their excellent stabilities in the human bodies. Said 1.beta.-methylcarbapenem derivatives have been synthesized by various processes up to now. In these processes, the following three kinds of compounds have been known as the important synthetic intermediates:
a) an azetidinone compound having a 1'-.beta.-methyl group at the 4-position of the azetidinone skeleton, i.e., a compound of the formula [A]: ##STR2## wherein R.sup.a is a hydroxy-substituted lower alkyl group which may be protected, PA0 b) a 1.beta.-methyl-2-oxocarbapenem compound of the formula [B]: ##STR3## wherein R.sup.b is a hydrogen atom or an ester residue, and R.sup.a is the same as defined above and PA0 c) a reactive derivative of the compound [B], i.e., a compound of the formula [C]: ##STR4## wherein a group of the formula: --OA.sup.a is an esterified hydroxy group, and R.sup.a and R.sup.b are the same as defined above. PA0 1) removing 1'-hydrogen atom of the acetic acid moiety located at the 4-position of the compound of the following formula: ##STR5## by using a strong base, 2) introducing methyl group to the product, PA0 3) hydrolyzing the product to give the compound [A] in which R.sup.a is 1-t-butyldimethylsilyloxyethyl group, PA0 4) subjecting the product to carbon atom increasing reaction, PA0 5) subjecting the product to diazotization, PA0 6) subjecting the product to intramolecular cyclization to give the compound [B] in which R.sup.a is 1-hydroxyethyl group and R.sup.b is p-nitrobenzyl group, and then PA0 7) subjecting the product to esterification to obtain the corresponding compound [C] [Heterocycles Vol. 21 p 29 (1984)]. PA0 (i) a step of reacting the compound [VIII] or a salt thereof with a thiol compound of the formula [IX]: EQU H--SR.sup.3 [IX] PA0 (ii) when R.sup.1 is a protected hydroxy-substituted lower alkyl group, an optional step for removing the protecting group and PA0 (iii) when R.sup.2 is an ester residue, an optional step for removing the ester residue.
As for a process for preparing these synthetic intermediates, there has been known a process which comprises the steps of:
However, the above process is unsatisfactory in that the yield of the compound having the 1'-methyl group with .beta.-configuration which shows an excellent pharmacological activity is low, because in preparing the compound [A] by the above process, said process is not a stereoselective synthetic process and the mixture of the compound [A] having the 1'-methyl group with .alpha.-configuration and .beta.-configuration is obtained. In recent years, therefore, various processes for stereoselectively preparing the compounds [A], [B] and [C] have been widely investigated and a typical process includes those utilizing the Aldol-type reaction or the Reformatsky-type reaction.
As for the process utilizing the Aldol-type reaction, for example, Japanese Patent Publication (unexamined) No. 252786 of 1987 discloses a process for the preparation of the compound [A] in which R.sup.a is t-butyldimethylsilyloxyethyl group, which comprises reacting a compound of the formula [D]: ##STR6## with a propionamide compound of the formula: ##STR7## in the presence of dibutylboron triflate to give a compound of the formula: ##STR8## and then hydrolyzing the product.
Further, Japanese Patent Publication (unexamined) No. 284176 of 1988 discloses a process for the preparation of the compounds [B] and [C], which comprises reacting the compound [D] with a compound of the formula: ##STR9## in the presence of tin triflate to give a compound of the formula: ##STR10## reacting the product with a compound of the formula: ##STR11## in the presence of imidazole, subjecting the product to diazotization, and then converting the product into the compound [B] or [C].
Moreover, Japanese Patent Publication (unexamined) Nos. 77384 of 1987, 169781 of 1987, 246550 of 1987 and 292269 of 1990 disclose the processes using the following compound instead of the above propionamide compound. ##STR12##
However, although such Aldol-type reactions can introduce the .beta.-methyl group stereoselectively, the processes are still unsatisfactory for the industrial scale production because expensive tin triflate or boron triflate must be used as a reagent in those reactions.
On the other hand, as for the process utilizing the Reformatsky-type reaction, for example, Japanese Patent Publication (unexamined) No. 178262 of 1990 discloses a process for the preparation of the compound [B] or [C], which comprises reacting the compound [D] with an .alpha.-bromopropionamide compound of the formula: ##STR13## wherein Tr is triphenylmethyl group, in the presence of zinc to give a compound of the formula [E]: ##STR14## wherein Tr is the same as defined above, hydrolyzing the product to give the compound [A] and then converting the product into the compound [B] or [C]. Further, Japanese Patent Publication (unexamined) Nos. 10765 of and 188662 of 1988 disclose the processes using the following compound instead of the above .alpha.-bromopropionamide compound. ##STR15##
However, the process utilizing the Reformatsky-type reaction has some defects in that .beta.-methyl group can not be introduced stereoselectively or in that it is difficult to synthesize the .alpha.-bromopropionic acid compound. Moreover, in order to convert the .beta.-methyl group-introduced product into the compound [B] or [C], it is necessary to once eliminate the group of the following formula: ##STR16## from said product and then activate the resulting compound by chemical modification, for example, by introducing a group which is suitable for the intramolecular cyclization.